CN103134891A - Measuring method of content of butyric acid clevidipine butyrate and content of related substances - Google Patents
Measuring method of content of butyric acid clevidipine butyrate and content of related substances Download PDFInfo
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- CN103134891A CN103134891A CN2011103920401A CN201110392040A CN103134891A CN 103134891 A CN103134891 A CN 103134891A CN 2011103920401 A CN2011103920401 A CN 2011103920401A CN 201110392040 A CN201110392040 A CN 201110392040A CN 103134891 A CN103134891 A CN 103134891A
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Abstract
Disclosed is a measuring method of the content of butyric acid clevidipine butyrate and the content of related substances. A high performance liquid chromatography is adopted, and octadecyl silane bonded silica gel is used as a reversed phase column of filler; ultraviolet detection is adopted, and detection wavelength is 230-250 nm; and a mobile phase A is acetonitrile, a mobile phase B is water, and the volume of the phase A accounts for 50%-90% of that of the mobile phases.
Description
Technical field:
The present invention relates to the assay method of a kind of butyrate clevidipine content and related substance.
Background technology:
Its chemical structural formula of clevidipine (Clevidipine, CAS:167221-71-8) is as follows:
Chemistry 4-(2,3-dichlorophenyl) by name-Isosorbide-5-Nitrae-dihydro-2,6-dimethyl-3,5-dipicolinic acid methyl (1-oxo butoxy) methyl ester is a kind of fugitive dihydropyridine calcium channel blocker.The butyrate clevidipine emulsion for injection is that Britain Astrazeneca AB develops, U.S. The Medicines Company company has it in exploitation and the commercialization mandate of the world market except Japan, and in August, 2008 first in U.S.'s listing this product, trade name Cleviprex, be used for the invalid hyperpietic's of unsuitable oral drugs or oral drugs treatment, after also can be used for treating operation, acute blood pressure raises, and this medicine is the first intravenous injection antihypertensive of drugs approved by FDA over 10 years.Animal experiment shows, it can descend mean arterial pressure by reducing systemic vascular resistance, to the VC blood vessel without effect.The III clinical trial phase of butyrate clevidipine intravenous injection emulsion has obtained the certainty result, studies show that, after Perioperative Hypertension patient medication in 15 minutes systolic pressure descend gradually, medication reached steady-state level after 15 minutes, after medication in 30 minutes changes in heart rate substantially steady, or slightly accelerate.
At present about the bibliographical information of the content assaying method of butyrate clevidipine seldom.The people such as Olle Gyllenhaal are at JChromatogr Nov 5 A.1999; 862 (1): reported in 95-104 to adopt and filled the purity that the pillar supercritical fluid chromatography detects clevidipine, yet the requirement of this method flow phase is harsher, equipment requirement is higher, and the prior application of supercritical fluid chromatography is to be used for to separate and preparation, application aspect analyzing and testing is also not universal, is not suitable for industrialized needs.In existing bibliographical information, have no other about the report of the assay method of butyrate clevidipine content and related substance.
Summary of the invention:
For overcoming defective of the prior art, this patent adopts high performance liquid chromatography, and using the most general anti-phase C18 post is the separation chromatography post, has realized the assay of butyrate clevidipine, and method is easy, accurate, good reproducibility.
The invention provides the assay method of a kind of butyrate clevidipine content and related substance:
A. be the reverse-phase chromatographic column of filling agent with octadecylsilane chemically bonded silica;
B. ultraviolet detects, and the detection wavelength is 230～250nm, is preferably 239～241nm, most preferably 240nm;
C. mobile phase A is acetonitrile mutually, and Mobile phase B is water mutually, and the volume ratio that A accounts for mobile phase mutually is 50%～90%, and is preferred 60%～80%, most preferably 70%;
D. chromatogram column temperature between 20～50 ℃, is preferably 30 ℃.
Preferably
Testing conditions is:
The detection wavelength is 240nm;
Detected temperatures is 30 ℃;
Mobile phase: the volume ratio of acetonitrile and water is 70: 30.
Or testing conditions is:
The detection wavelength is 239nm;
Detected temperatures is 30 ℃;
Mobile phase: the volume ratio of acetonitrile and water is 60: 40.
Or testing conditions is:
The detection wavelength is 241nm;
Detected temperatures is 40 ℃;
Mobile phase: the volume ratio of acetonitrile and water is 80: 20.
The analytical approach that the present invention mentions, its flow rate of mobile phase are set as the known general knowledge of those skilled in the art.Common scope is generally between 0.5ml/min to 2ml/min.
The chromatogram that the analytical approach that the present invention mentions obtains is the normalization method liquid chromatogram of specimen, obtained the normalization method liquid content of specimen, use same analytical approach, the normalization method liquid content of the reference substance that can obtain testing, then calculate the liquid content that can obtain butyrate clevidipine by external standard method, can measure related substance by Self-control method.
" chemicals Quality Control Analysis method validation technological guidance principle " ([H] GPH5-1) that promulgate according to State Food and Drug Administration carries out the methodology checking to above-mentioned analysis condition, proves that content and the related substance of the method mensuration butyrate clevidipine complies with relevant regulations.
The efficient liquid-phase chromatography method of the content detection of butyrate clevidipine provided by the invention has following advantage:
(1) use common octadecylsilane chemically bonded silica to be the chromatographic column of filling agent, equipment requirement is not high.
(2) mobile phase is selected acetonitrile and water, two common being easy to get of medium, and feasibility is high.
(3) operating process is simple and convenient, accurately, and good reproducibility.
(4) applicability is good, can detect simultaneously content and the related substance of butyrate clevidipine.
Description of drawings:
Fig. 1: embodiment 1 gained liquid chromatogram
Fig. 2: embodiment 2 gained liquid chromatograms
Fig. 3: embodiment 3 gained liquid chromatograms
Fig. 4: embodiment 4 gained liquid chromatograms
Fig. 5: embodiment 5 gained liquid chromatograms
Embodiment:
The below will the invention will be further described by embodiment, and these descriptions are not that content of the present invention is done further to limit.Person skilled should be understood that and is equal to replacement to what technical characterictic of the present invention was done, or corresponding the improvement, within still belonging to protection scope of the present invention.
The reference substance of butyrate clevidipine reaches 99.90% for the self-control sample by internal mark method determination content.
The configuration of sample solution: precision measures each 20.0mg of butyrate clevidipine sample 1-5, is placed in the 100ml measuring bottle, after adding the dissolving of appropriate acetonitrile-water (7: 3) mixed solution, is diluted to scale with acetonitrile-water (7: 3) mixed solution.
The configuration of content reference substance solution: precision measures butyrate clevidipine reference substance 20.0mg, is placed in the 100ml measuring bottle, after adding the dissolving of appropriate acetonitrile-water (7: 3) mixed solution, is diluted to scale with acetonitrile-water (7: 3) mixed solution.
The configuration of impurity reference substance solution: the above-mentioned content reference substance solution of separately getting 1ml is diluted to the 100ml volumetric flask with acetonitrile-water (7: 3) mixed solution.
With above-mentioned sample solution and reference substance solution difference sample introduction, provide HPLC to analyze according to following condition, external standard method is calculated butyrate clevidipine content, and Self-control method detects related substance.
Embodiment 1
Chromatographic condition:
High performance liquid chromatograph: Waters-2489-2695
Detecting device: UV-detector detects wavelength: 240nm
Sample size: 20.0 μ l column temperatures: 30 ℃
Flow velocity: the 1ml/min post is pressed: 1250psi
Chromatographic column: Agilent, C18,5 μ m, 4.6 * 250mm
Analytical balance: 100,000/, Sartorius BS21S
Mobile phase: acetonitrile: water=70: 30
Measurement result (Fig. 1):
| Title | Retention time (minute) | Content (%) |
| Butyrate clevidipine | 7.771 | 99.88 |
| Impurity 1 | 3.865 | 0.05 |
| Impurity 2 | 6.136 | 0.03 |
| Impurity 3 | 10.118 | 0.04 |
Embodiment 2
Chromatographic condition:
High performance liquid chromatograph: Waters-2489-2695
Detecting device: UV-detector detects wavelength: 230nm
Sample size: 20.0 μ l column temperatures: 50 ℃
Flow velocity: the 1ml/min post is pressed: 1250psi
Chromatographic column: Agilent, C18,5 μ m, 4.6 * 250mm
Analytical balance: 100,000/, Sartorius BS21S
Mobile phase: acetonitrile: water=50: 50
Measurement result (Fig. 2):
| Title | Retention time (minute) | Content (%) |
| Butyrate clevidipine | 8.025 | 99.73 |
| Impurity 1 | 3.133 | 0.01 |
| Impurity 2 | 5.764 | 0.15 |
| Impurity 3 | 11.690 | 0.11 |
Embodiment 3
Chromatographic condition:
High performance liquid chromatograph: Waters-2489-2695
Detecting device: UV-detector detects wavelength: 239nm
Sample size: 20.0 μ l column temperatures: 30 ℃
Flow velocity: the 1ml/min post is pressed: 1250psi
Chromatographic column: Agilent, C18,5 μ m, 4.6 * 250mm
Analytical balance: 100,000/, Sartorius BS21S
Mobile phase: acetonitrile: water=60: 40
Measurement result (Fig. 3):
| Title | Retention time (minute) | Content (%) |
| Butyrate clevidipine | 7.829 | 99.90 |
| Impurity 1 | 3.890 | 0.03 |
| Impurity 2 | 6.177 | 0.03 |
| Impurity 3 | 10.202 | 0.04 |
Embodiment 4
Chromatographic condition:
High performance liquid chromatograph: Waters-2489-2695
Detecting device: UV-detector detects wavelength: 250nm
Sample size: 20.0 μ l column temperatures: 20 ℃
Flow velocity: the 1ml/min post is pressed: 1250psi
Chromatographic column: Agilent, C18,5 μ m, 4.6 * 250mm
Analytical balance: 100,000/, Sartorius BS21S
Mobile phase: acetonitrile: water=90: 10
Measurement result (Fig. 4):
| Title | Retention time (minute) | Content (%) |
| Butyrate clevidipine | 7.263 | 99.50 |
| Impurity 1 | 3.892 | 0.05 |
| Impurity 2 | 5.823 | 0.27 |
| Impurity 3 | 9.311 | 0.18 |
Embodiment 5
Chromatographic condition:
High performance liquid chromatograph: Waters-2489-2695
Detecting device: UV-detector detects wavelength: 241nm
Sample size: 20.0 μ l column temperatures: 40 ℃
Flow velocity: the 1ml/min post is pressed: 1250psi
Chromatographic column: Agilent, C18,5 μ m, 4.6 * 250mm
Analytical balance: 100,000/, Sartorius BS21S
Mobile phase: acetonitrile: water=80: 20
Measurement result (Fig. 5):
| Title | Retention time (minute) | Content (%) |
| Butyrate clevidipine | 7.452 | 99.19 |
| Impurity 1 | 3.942 | 0.02 |
| Impurity 2 | 5.943 | 0.58 |
| Impurity 3 | 9.611 | 0.21 |
Claims (10)
1. the assay method of a butyrate clevidipine content and related substance, it is characterized in that: be the reverse-phase chromatographic column of filling agent with octadecylsilane chemically bonded silica, the detection wavelength is 230～250nm, mobile phase A is acetonitrile mutually, Mobile phase B is water mutually, and the volume ratio that A accounts for mobile phase mutually is 50%～90%.
2. the assay method of butyrate clevidipine content as claimed in claim 1 and related substance, it is characterized in that: detection wavelength used is preferably 239～241nm.
3. the assay method of butyrate clevidipine content as claimed in claim 2 and related substance, it is characterized in that: detection wavelength used most preferably is 240nm.
4. the assay method of butyrate clevidipine content as claimed in claim 1 and related substance, it is characterized in that: the volume ratio that mobile phase A accounts for mobile phase mutually is preferably 60%～80%.
5. the assay method of butyrate clevidipine content as claimed in claim 4 and related substance, it is characterized in that: the volume ratio that mobile phase A accounts for mobile phase mutually most preferably is 70%.
6. the assay method of described butyrate clevidipine content as arbitrary in claim 1～5 and related substance, it is characterized in that: chromatogram column temperature is between 20～50 ℃.
7. the assay method of butyrate clevidipine content as claimed in claim 6 and related substance, it is characterized in that: chromatogram column temperature is preferably 30 ℃.
8. the assay method of butyrate clevidipine content as claimed in claim 1 and related substance, it is characterized in that: testing conditions is as follows:
The detection wavelength is 240nm;
Detected temperatures is 30 ℃;
Mobile phase: the volume ratio of acetonitrile and water is 70: 30.
9. the assay method of butyrate clevidipine content as claimed in claim 1 and related substance, it is characterized in that: testing conditions is as follows:
The detection wavelength is 239nm;
Detected temperatures is 30 ℃;
Mobile phase: the volume ratio of acetonitrile and water is 60: 40.
10. the assay method of butyrate clevidipine content as claimed in claim 1 and related substance, it is characterized in that: testing conditions is as follows:
The detection wavelength is 241nm;
Detected temperatures is 40 ℃;
Mobile phase: the volume ratio of acetonitrile and water is 80: 20.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104458937A (en) * | 2014-11-20 | 2015-03-25 | 北京京科泰来科技有限公司 | Method for detecting related substances in cleviprex fat emulsion |
| CN104597192A (en) * | 2014-12-31 | 2015-05-06 | 武汉科福新药有限责任公司 | Method for detecting clevidipine butyrate and related substances in preparations of clevidipine butyrate |
| CN104833670A (en) * | 2015-05-13 | 2015-08-12 | 中国人民解放军第二军医大学 | Real-time monitoring method for clevidipine butyrate crude drug synthesis process |
| CN105092769A (en) * | 2015-01-15 | 2015-11-25 | 上海馨平医药科技发展有限公司 | Method for simultaneously detecting clevidipine butyrate and related substances |
| CN107367569A (en) * | 2016-05-13 | 2017-11-21 | 天津康鸿医药科技发展有限公司 | A kind of detection method of butyrate clevidipine about material |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010014234A1 (en) * | 2008-08-01 | 2010-02-04 | The Medicines Company | Pharmaceutical compositions and methods for stabilizing the same |
| CN102170786A (en) * | 2008-08-01 | 2011-08-31 | 医药公司 | Pharmaceutical compositions and methods for producing low impurity concentrations of the same |
-
2011
- 2011-11-30 CN CN2011103920401A patent/CN103134891A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010014234A1 (en) * | 2008-08-01 | 2010-02-04 | The Medicines Company | Pharmaceutical compositions and methods for stabilizing the same |
| CN102170786A (en) * | 2008-08-01 | 2011-08-31 | 医药公司 | Pharmaceutical compositions and methods for producing low impurity concentrations of the same |
Non-Patent Citations (3)
| Title |
|---|
| OLLE GYLLENHAAL ET AL: "Packed-column supercritical fluid chromatography for the purity analysis of clevidipine, a new dihydropyridine drug", 《JOURNAL OF CHROMATOGRAPHY A》 * |
| 张婧 等: "氯维地平的合成", 《中国医药工业杂志》 * |
| 邓超 等: "丁酸氯维地平成品中杂质的合成与结构鉴定", 《现代药物与临床》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104458937A (en) * | 2014-11-20 | 2015-03-25 | 北京京科泰来科技有限公司 | Method for detecting related substances in cleviprex fat emulsion |
| CN104597192A (en) * | 2014-12-31 | 2015-05-06 | 武汉科福新药有限责任公司 | Method for detecting clevidipine butyrate and related substances in preparations of clevidipine butyrate |
| CN105092769A (en) * | 2015-01-15 | 2015-11-25 | 上海馨平医药科技发展有限公司 | Method for simultaneously detecting clevidipine butyrate and related substances |
| CN104833670A (en) * | 2015-05-13 | 2015-08-12 | 中国人民解放军第二军医大学 | Real-time monitoring method for clevidipine butyrate crude drug synthesis process |
| CN104833670B (en) * | 2015-05-13 | 2017-08-01 | 中国人民解放军第二军医大学 | A kind of method of real-time of butyrate clevidipine bulk drug building-up process |
| CN107367569A (en) * | 2016-05-13 | 2017-11-21 | 天津康鸿医药科技发展有限公司 | A kind of detection method of butyrate clevidipine about material |
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Application publication date: 20130605 |